RSC Publishing. Principles and Applications. In Silico Toxicology. Liverpool John Moores University, Liverpool, Edited by

Transcription

1 In Silico Toxicology Principles and Applications Edited by Mark T. D. Cronin and Judith C. Madden Liverpool John Moores University, Liverpool, UK RSC Publishing

2 Contents Chapter 1 In Silico Toxicology An Introduction 1 M. T. D. Cronin and J. C. Madden 1.1 Introduction Factors that Have Impacted on In Silico Toxicology: the Current State-of-the-Art Types of In Silico Models Uses of In Silico Models How to Use this Book Acknowledgements 9 References 9 Chapter 2 Introduction to QSAR and Other In Silico Methods to Predict Toxicity 11 J. C. Madden 2.1 Introduction Building an In Silico Model Assessing the Validity of the Model Reviewing and Updating the Model Using the Model Consideration of Mitigating Factors Documenting the Process Pitfalls in Generating and Using QSAR Models Conclusions Acknowledgements 29 References 29 Issues in Toxicology No.7 In Silico Toxicology: Principles and Applications Edited by Mark T. D. Cronin and Judith C. Madden The Royal Society of Chemistry 2010 Published by the Royal Society of Chemistry,

3 Chapter 3 Finding the Data to Develop and Evaluate (Q)SARs and Populate Categories for Toxicity Prediction 31 M. T. D. Cronin 3.1 Introduction Which Data Can be Used for In Silico Modelling? Uses of Data How Many Data are Required? Sources of Data Retrieving Publicly Available Toxicity Data and Information for In Silico Modelling Ongoing Data Compilation Activities Ensuring Success in Using Toxicity Data in In Silico Models: Hierarchy of Data Consistency and Quality Case Studies Conclusions and Recommendations Acknowledgements 56 References 56 Chapter 4 Data Quality Assessment for In Silico Methods: A Survey of Approaches and Needs 59 M. Nendza, T. Aldenberg, E. Benfenati, R. Benigni, M.T.D. Cronin, S. Escher, A. Fernandez, S. Gabbert, F. Giralt, M. Hewitt, M. Hrovat, S. Jeram, D. Kroese, J. C. Madden, I. Mangelsdorf, R. Rallo, A. Roncaglioni, E. Rorije, H. Segner, B. Simon-Hettich and T. Vermeire 4.1 Introduction Principles of Data Quality Assessment Biological Data Variability Checklist Approach Endpoint-Specific Considerations of Inherent Data Variability Integration of Data with Distinct Degrees of Reliability Cost-Effectiveness Analysis of Tests and Testing Systems Acknowledgements 111 References 111 Chapter 5 Calculation of Physico-Chemical and Environmental Fate Properties 118 T. H. Webb and L. A. Morlacci 5.1 Introduction Getting the Most Out of Estimation Methods 119

4 5.3 Selected Software for the Estimation of Physico-Chemical and Environmental Fate Properties Physico-Chemical Property Estimations Environmental Fate Properties Conclusions 143 References 144 Chapter 6 Molecular Descriptors from Two-Dimensional Chemical Structure 148 U. Maran, S. Sild, I. Tulp, K. Takkis and M. Moosus 6.1 Introduction Mathematical Foundation of 2-D Descriptors Navigation Among 2-D Descriptors Examples of Use Interpretation of 2-D Descriptors Sources for the Calculation of 2-D Descriptors Conclusions Literature for In-Depth Reading Acknowledgements 188 References 189 Chapter 7 The Use of Frontier Molecular Orbital Calculations in Predictive Reactive Toxicology 193 S. J. Enoch 7.1 Introduction Mechanistic Chemistry Commonly Utilised Quantum Mechanical Descriptors and Levels of Computational Theory Descriptors Derived from Frontier Molecular Orbitals Isomers and Conformers Chemical Category Formation and Read-Across Quantum Chemical Calculations Conclusions Acknowledgements 207 References 207 Chapter 8 Three-Dimensional Molecular Modelling of Receptor-Based Mechanisms in Toxicology 210 J. C. Madden and M. T. D. Cronin 8.1 Introduction Background to 3-D Approaches Modelling Approaches for Receptor-Mediated Toxicity 213

5 8.4 Ligand-Based Approaches Receptor-Based approaches Examples of the Application of 3-D Approaches in Predicting Receptor-Mediated Toxicity Advantages and Disadvantages of 3-D Methods Conclusions and Future Outlook Acknowledgements 226 References 226 Chapter 9 Statistical Methods for Continuous Measured Endpoints in In Silico Toxicology 228 P. H. Rowe 9.1 Continuous Measured Endpoints (Interval Scale Data) Regression Analysis Models in QSAR Principal Components Regression (PCR) Partial Least Squares (PLS) Regression Conclusions 250 References 250 Chapter 10 Statistical Methods for Categorised Endpoints in In Silico Toxicology 252 P. H. Rowe 10.1 Ordinal and Nominal Scale Endpoints and Illustrative Data Discriminant Analysis Logistic Regression k-nearest-neighbour(s) Choice of Method for Categorised Data Conclusions 273 References 273 Chapter 11 Characterisation, Evaluation and Possible Validation of In Silico Models for Toxicity: Determining if a Prediction is Valid 275 M. T. D. Cronin 11.1 Introduction A Very Brief History OECD and European Chemicals Agency Documents and Further Background Papers and Sources of Information Definition of Terms OECD Principles for the Validation of (Q)SARs 283

6 11.6 Examples of Validation of (Q)SARs from the Literature Describing a QSAR: Use of the QSAR Model Reporting Format Case Studies: Application of the OECD Principles Is the Prediction Valid? Conclusions and Recommendations Acknowledgements 298 References 299 Chapter 12 Developing the Applicability Domain of In Silico Models: Relevance, Importance and Methods 301 M. Hewitt and C. M. Ellison 12.1 Introduction Regulatory Context Applicability Domain Definition Case Study Recommendations Acknowledgements 330 References 330 Chapter 13 Mechanisms of Toxic Action in In Silico Toxicology 334 D. W. Roberts 13.1 Introduction Modes and Mechanisms Reaction Mechanistic Domains Mechanism-Based Reactivity Parameters for Electrophilic Toxicity Role of Hydrophobicity in Modelling Electrophilic Toxicity Conclusions Acknowledgements 344 References 344 Chapter 14 Adverse Outcome Pathways: A Way of Linking Chemical Structure to In Vivo Toxicological Hazards 346 T. W. Schultz 14.1 Categories in Hazard Assessment Filling Data Gaps in a Category Mechanism of Toxic Action Toxicologically Meaningful Categories (TMCs) The Concept of the Adverse Outcome Pathway Weak Acid Respiratory Uncoupling 354

7 14.7 Respiratory Irritation Skin Sensitisation Acetylcholinesterase Inhibition Receptor Binding Pathways for Phenolic Oestrogen Mimics Using Pathways to Form TMCs and Reduce Testing Hazards with Elaborate Datasets Pathways for Elaborate Hazard Endpoints Positive Attributes of the Adverse Outcome Pathway Approach Conclusions: Basic Elements in Developing a Pathway 367 References 368 Chapter 15 An Introduction to Read-Across for the Prediction of the Effects of Chemicals 372 S. Dimitrov and O. Mekenyan 15.1 Read-Across Basis of Performing Read-Across Practical Aspects of Read-Across Example: Read-Across for the Prediction of the Toxicity of 4-Ethylphenol to Tetrahymenapyriformis Conclusions 383 References 383 Chapter 16 Tools for Category Formation and Read-Across: Overview of the OECD (Q)SAR Application Toolbox 385 R. Diderich 16.1 The OECD (Q)SAR Project: From Validation Principles to an Application Toolbox Workflow of the Toolbox Example Use Scenarios for Regulatory Application Conclusions and Outlook 404 References 405 Chapter 17 Open Source Tools for Read-Across and Category Formation 408 N. Jeliazkova, J. Jaworska and A. P. Worth 17.1 Introduction Open Source, Open Data and Open Standards in Chemoinformatics Descriptions of the Tools Suitable for Category Formation and Read-Across 417

8 17.4 Summary and Conclusions Acknowledgements 442 References 443 Chapter 18 Biological Read-Across: Mechanistically-Based Species-Species and Endpoint-Endpoint Extrapolations 446 M. T. D. Cronin 18.1 Introduction Extrapolation of Toxicological Information from One Species to Another Prediction Models Examples of Extrapolation of Toxicity Between Species: Acute Aquatic Toxicity Endpoint-to-Endpoint Read-Down of Toxicity: Extrapolation of Toxicity Between Effects US Environmental Protection Agency Web-Based Inter-species Correlation Estimation (Web-ICE) Application Recent Developments Conclusions Acknowledgments 474 References 474 Chapter 19 Expert Systems for Toxicity Prediction 478 /. C. Dearden 19.1 Introduction Available Expert Systems Independent Comparative Assessment of Software Performance Consensus Modelling Software Performance with Tetrahymena pyriformis Test Set Software Performance with Skin Sensitisation Test Set Conclusions Acknowledgments 502 References 502 Chapter 20 Exposure Modelling for Risk Assessment 508 J. Marquart 20.1 Introduction: Hazard, Exposure, Risk Types of Exposure Estimates used in Risk Characterisation in REACH 510

9 20.3 Methods for Exposure Assessment in Regulatory Processes 512 Models Types of Human Exposure 20.5 Detailed Description of the Models Advantages and Disadvantages of the Models Conclusions 528 References 528 Chapter 21 Toxicokinetic Considerations in Predicting Toxicity 531 /. C. Madden 21.1 Introduction Internal Exposure Predicting ADME Parameters Physiologically-Based Toxicokinetic Modelling Conclusions and Outlook Acknowledgements 554 References 554 Chapter 22 Multiple Test In Silico Weight-of-Evidence for Toxicological Endpoints 558 T. Aldenberg and J. S. Jaw orska 22.1 Introduction Two-Test Training Dataset One-Test Bayesian Inference Two-Test Battery Bayesian Inference Two-Test Data Fitting and Model Selection Conclusions 580 References 581 Chapter 23 Integrated Testing Strategies and the Prediction of Toxic Hazard 584 M. Balls 23.1 Introduction Essential Nature and Uses of ITS Historical Development of the Concept of ITS ITS and Risk Assessment In Vitro Methods for Use in ITS Evaluation and Application of ITS Securing the Regulatory Acceptance of ITS 600 References 603

10 Chapter 24 Using In Silico Toxicity Predictions: Case Studies for Skin Sensitisation 606 M. T. D. Cronin and J. C. Madden 24.1 Introduction Forming a Consensus: Integrating Predictions Choice of Chemicals for Analysis In Silico Prediction Methods and In Chemico Data Existing Data, In Silico Predictions and In Chemico Data for 4-Amino-2-Nitrophenol In Silico Predictions and In Chemico Data for 1,14-Tetradecanediol Conclusions and Recommendations Acknowledgements 620 References 621 Appendix Appendix Subject Index 659